Designer Sperm Passes Selected Genes to Future Generations

Frustrated by slow progress in gene therapy, a team of scientists opted for an unconventional approach. Instead of relying on the oocyte as a substrate for genetic modification, they took a closer look at male germ cells, including mature sperm. Sperm, owing to their accessibility, seemed to offer a convenient route to transgenesis.

The scientists, based at the Royal Veterinary College in North Mimms, United Kingdom, used a viral vector to insert genetic material into mouse spermatozoa. Then the spermatozoa were used in an in vitro fertilization procedure. In the resulting embryos, the genetic material was found to be present and active—and inheritable. The genetic material that had been introduced to the spermatozoa was, the scientists confirmed, still functional after passing through at least three generations of mice.

The scientists presented their results December 2 in The FASEB Journal, in an article entitled “Efficient generation of transgenic mice by lentivirus-mediated modification of spermatozoa.” In this article, the authors wrote, “When pseudotyped lentiviral vectors encoding green fluorescent protein (GFP) were incubated with mouse spermatozoa, these sperm were highly successful in producing transgenics.” Then, after embryo transfer, “≥42% of founders were found to be transgenic for GFP.”

The authors also noted that they used inverse PCR for integration site analysis, which allowed them to show that at least one or two copies of GFP had been integrated in the transgenic animals, mapping to different chromosomes. GFP expression was detected in a wide range of murine tissues, including testis.

This transgenic technology—if successful in humans—could lead to a new frontier in genetic medicine in which diseases and disorders are effectively cured, and new human attributes, such as organ regeneration, may be possible.

“Transgenic technology is a most important tool for researching all kinds of disease in humans and animals, and for understanding crucial problems in biology,” said Anil Chandrashekran, Ph.D., a study author and research associate at the Royal Veterinary College.

In detailing the more immediate applications of their work, the authors wrote, “This relatively simple, yet highly efficient, technique for generating transgenic animals by transducing spermatozoa with lentiviral vectors in vitro is a powerful tool for the study of fertilization/preimplantation development, vertical viral gene transmission, gene function and regulation, and epigenetic inheritance.

Offering a more expansive view of the authors’ work, Gerald Weissmann, M.D., editor-in-chief of The FASEB Journal, noted that using modified sperm to insert genetic material has the potential to be a major breakthrough not only in future research, but also in human medicine.

“It facilitates the development of transgenic animal models, and may lead to therapeutic benefits for people as well,” said Dr. Weissman. “For years we have chased effective gene therapies and have hit numerous speed bumps and dead ends. If we are able to able to alter sperm to improve the health of future generations, it would completely change our notions of ‘preventative medicine.'”